Understanding the basic, biological mechanisms of a disease often begins with unveiling a genetic alteration that either directly causes cells to malfunction or makes them more likely to do so in the presence of environmental factors. The powerful new tools of the Human Genome Project (HGP) have made finding disease genes considerably faster and cheaper than before, and have put many scientists on the path to understanding exactly how gene alterations cause disease.

For diseases caused by alterations in just one gene, such as cystic fibrosis, Huntington's disease, or Marfan syndrome, the journey goes like this: Find the gene; determine what protein the gene instructs the cell to make; and learn what role that protein plays in cell function. Translating this information into treatments or cures, of course, is the key reason why scientists want to find genes.

But the so-called diseases of civilization - complex disorders, such as high blood pressure and other familiar diseases of the heart and circulatory system, diabetes, obesity, cancer, psychiatric illness, asthma, arthritis - pose difficult health problems because scientists have very little information about what causes them and even less about how to prevent or cure them. Indeed, complex disorders are common among people living in developed countries. Half of U.S. deaths - a million every year - are due to diseases of the heart and circulation, and cancer is responsible for another 25 percent. Sixteen million Americans are said to suffer from diabetes, a major cause of death and a leading reason for disabling limb and nerve damage, kidney failure and blindness. Alzheimer's disease, the most common mental impairment among the elderly, afflicts up to four million Americans.

The main reason such diseases are so hard to figure out (and why scientists call them complex) is because almost all involve more than one gene, and the genes interact with each other and/or with one or more aspects of the outside world - for example a virus or some component of diet - to produce disease.

Complex disorders have unusual inheritance patterns

In the past when people referred to "genetic disease," they were talking about disorders that arise from a mutation in just one of the 80,000 or so genes in a human cell. Sickle-cell disease and Tay-Sachs are examples of such disorders. Researchers have catalogued some 4,000 diseases they believe are caused by alterations in a single gene. Most of these diseases are not common, but by scientific standards, they are among the easiest to figure out. They abide by tried and true genetic laws when they are passed from one generation to the next, so tracking the genes that cause the disorder through families is relatively easy. Although complex disorders also cluster in families, there are no clear-cut rules yet to explain why some family members develop them while others remain healthy.

Complex traits may resemble each other - but for different reasons

With complex disorders, several things make it difficult to determine the genetic roots of a disease. For one, environmental substances can sometimes produce the same health problems as an altered gene. This type of mimicry has been a serious problem in particular for defining the genetic contributions to psychiatric illnesses, because a particular symptom - hallucinations, for example - can also be triggered by outside events such as recreational drug use. In another example, scientists have identified a number of gene mutations that disrupt the normal rhythms of the heart. These genetic alterations no doubt account for a sizeable proportion of deaths due to cardiac arrhythmias. But scientists have also identified several other causes of abnormal heart rhythms: antihistamines, anesthetics - and, most commonly, coronary artery disease.

Second, complex disorders can share symptoms with other diseases, making it hard to correctly identify the disorder. This in turn makes it hard to determine if everyone with a certain disease trait has the same underlying physiological problems. Studying a group that contains people who have similar symptoms but for different biological reasons can send a gene hunter on a wild goose chase. This, too, has been a serious problem for the study of psychiatric illness. In the past it was common for psychiatrists in different countries to use different criteria to define, say, schizophrenia. An international genetics study of people with schizophrenia, then, might contain individuals who had similar symptoms but radically different biological causes, and therefore, different genetic bases. Although diagnosing psychiatric illness is much more uniform today, this type of confusion still poses a challenge for scientists trying to determine the underlying genetics of a common disorder.

Third, complex disorders are almost always caused by alterations in more than one gene. Researchers have identified 19 different regions of the genome possibly related to multiple sclerosis, for example, although only a fraction are likely to cause disease in any one person. Inherited breast cancer has already been traced to mutations in three different genes, and the experts expect at least one additional breast cancer gene to be identified eventually. One study identified at least five gene sites associated with the juvenile form of diabetes, while recently, scientists identified three genes associated with the adult form. In the laboratory mouse, at least 15 genes on 10 different chromosomes are now known to affect the risk of diabetes. Despite the heavy contribution of gene mutations to the various forms of diabetes, environmental factors such as diet, of course, are still important.

Finally, inheriting a gene mutation associated with a disorder is no guarantee a person will develop that disorder. The likelihood of developing the disease can be very low, or in some cases, nearly 100 percent. Some people may develop mild forms that require no treatment or severe forms that resist all medicine has to offer. This phenomenon is modified by environmental factors or the actions of other genes.

Power in numbers helps unravel complex disorders

How will scientists identify the many genes that contribute to a complex disease? And how will they sort out which symptoms result from genetics or environment? One promising method for studying the genetic basis of complex disorders is a genome-wide approach to gene mapping known as genotyping.

A person's genotype refers to his or her own arrangement of the DNA letters, A, T, C, or G, in a particular region of their genome. The arrangement may be different from one person to the next. If one person is sick with an inherited disorder and another isn t, the cause may lie in differences in a particular spot in their DNA.

In complex disorders, several such alterations each contribute only a small part to the overall development of the disease. These subtle genetic influences are harder to pick out than are the effects of a single gene in a Mendelian disorder, for example. So, scientists looking for genetic contributions to complex disorders usually must analyze the genotypes of many hundreds of people for each disease they study.

Determining the genotypes at 300 to 400 locations in a person's DNA will provide dense enough sampling to identify candidate regions - places likely to contain genes related to the disease. That means hundreds of thousands of genotypes must be performed to find all the regions that contain genes related to a particular disease.

Genotyping methods make the task more efficient by using machines and computer technology to determine DNA spelling differences in hundreds of thousands of genotypes. In addition, genotyping for complex disorders often focuses particularly on family members who are ill rather than on all family members like other gene-finding techniques. A standard approach uses genotype information from two or more siblings who have the same disorder. That's because the laws of inheritance say any two siblings usually share half of their genetic makeup. But, if, say, two sisters have both inherited the same disease, they will share the portion of their genetic makeup near the disease gene more often than half the time. Scientists can use genotyping to detect those regions and search them for the gene mutations that are contributing to the siblings disorder.

And then there's the environment

And what about the all-important role of environmental factors? Genetic susceptibility may be necessary, but is not sufficient to produce most cases of obesity, cardiovascular disease, arthritis, asthma, cancer and infectious diseases. All of these common disorders usually require input from the world outside, such as high-fat diet, lack of exercise, smoking or exposure to allergens, carcinogens or infectious agents.

Changes in lifestyle can greatly influence the effects of genes, and so can change the occurrence of complex disorders in a given population. Recent shifts in diet, exercise patterns and possibly social stress may help explain why diabetes has become increasingly common among Native Americans and the high rates of hypertension among African Americans. An increase in exposure to sunlight helps account for an upsurge in the deadly skin cancer melanoma among people of Northern European descent.

By sorting out which aspects of a disease are most influenced by genetics, scientists can get a better handle on the environmental factors that trigger complex disorders. Indeed, modifying the environment may be among the easiest and most cost-effective ways to prevent illness. In any case, a better understanding of the role both of these forces in human disease will give people their best chance ever of a healthier modern life.